1. Field of the Invention
The present invention relates to stable budesonide solutions, the process for their preparation, and their use for producing pharmaceutical preparations, in particular enemas and pharmaceutical foams.
2. Background Art
Budesonids (INN; 16.alpha.,17-butylidenedioxy-11.beta.,21-dihydroxy-1,4-pregnadiene-3,20-di one) is a known active substance of the corticoid series which is employed in particular for the treatment of bronchial disorders, but also in cases of inflammatory bowel disorders such as Crohn's disease and, in particular, ulcerative colitis. It has proven particularly suitable for the last-mentioned indication to administer rectal drug forms such as enema preparations or pharmaceutical foams in compressed gas packs, because the active substance is employed directly at the site of the disorder, and budesonide is especially topically effective.
Budesonide is a racemate consisting of a mixture of the two diastereomers 22R and 22S. The racemate can be employed for the purposes of the present invention, but the 22R diastereomer is preferably employed because this is more active in pharmacological respects by a factor of about 2-3. Processes for fractionating the enantiomers are known, for example from EPA 92.901023.9.
Because of its lipophilicity, budesonide is virtually insoluble in water but is readily soluble in alcohols. An adequate amount of active substance can be dissolved by the use of solubilizers such as organic, water-soluble alcohols. However, the solutions obtained in this way prove to have too little stability for pharmaceutical use because large amounts of the active substance are decomposed within a short time.
Because of this instability, budesonide preparations which can be used directly by the patient in the administration form ready for use are unknown. Although budesonide-containing enemas are currently marketed in some countries, in these cases the enemas are not ready for use but comprise a type of combination of tablets containing active substance and enema bottles filled with water. Before administration, the patient must in each case remove a tablet, introduce it into the opened enema bottle, wait until the tablet has disintegrated and shake the bottles vigorously before use in order to disperse the active substance as homogeneously an possible in the form of a suspension.
This laborious and troublesome preparation of the enema ready for use can be only inadequately accomplished in particular by frail patients. Homogeneous dispersion of the active substance can be achieved only inadequately by this process, and complete administration of the active substance by squeezing of the enema bottle can scarcely be guaranteed because there is a tendency for the suspended active substance to settle out on the bottom of the bottle in a short time after preparation of the final form.
Although rectal administration of budesonide by means of rectal foams has advantages in respect of convenience of use, the problem here is to provide budesonide solutions which have adequate stability for administration in compressed gas packs. Budesonide-containing rectal foams have therefore not hitherto been disclosed.